There is a very high incidence of treatment resistance in bipolar illness. Some two thirds of patients in academic centers remain highly symptomatic despite aggressive pharmacotherapy. Days depressed exceed days manic by a factor of three. It is from this large pool of highly treatment-refractory patients that the Branch seeks to better understand the differential pathophysiological mechanisms in recurrent unipolar and bipolar affective disorders and develop new therapeutic modalities. A recently completed study is a double-blind, randomized trial of six weeks of treatment with an agent that enhances inhibitory GABAergic function (gabapentin, GPN), versus one that decreases excitatory glutamatergic function (lamotrigine, LTG), versus placebo, with patients crossing over to the other drug treatments in order to ascertain differential clinical response. This study found significant benefit of LTG (20/39 or 51% response rate) over GPN (11/40 or 28%) and placebo (8/28 or 21%). Correlates of lamotrigine response included male gender, bipolarity, fewer prior clinical trials, and fewer prior hospitalizations for depression. Preliminary evidence suggests that a baseline pattern of hypo-perfusion on 0-15 PET was associated with clinical response. In relationship to the assessment of possible predictors of clinical response, depressed patients with global hypermetabolism on PET, especially in the left insula, are more likely to be responsive to carbamazepine (N=26), while those with the more classic pattern of frontal and left insula hypometabolism are more likely to be responsive to the dihydropyridine L-type calcium channel blocker nimodipine. We have found that nimodipine increases somatostatin in cerebrospinal fluid (CSF) and those with lower CSF somatostatin at baseline are more likely to respond clinically. The major treatment initiative in the Branch is now the use of repeated transcranial magnetic stimulation (rTMS) of the brain for the treatment of depression. Two of the first six patients responded in a pilot study of 20 Hz stimulation at 80% of motor threshold of left frontal cortex. A double-blind, randomized, crossover trial then indicated significant antidepressant effects of active rTMS for two weeks compared with the sham (George et al, 1998). The next study assessed the differential responsivity to low-frequency (1 Hz) vs. higher frequency (20 Hz) rTMS vs. sham stimulation over left frontal cortex at 80% of motor threshold (MT). This study found differential clinical and metabolic responses within the same patient to these different frequencies. Moreover, those with a pattern of baseline hypometabolism tend to respond to the 20 Hz stimulation, while those with baseline patterns of hypermetabolism are more likely to respond to the 1 Hz stimulation. Because the incidence and magnitude of clinical responsivity was not adequate for many patients, a fourth study using higher intensities (100% of MT) was completed. This study replicated the findings of differential responsivity within individual patients and revealed that 20 Hz stimulation increased 0-15 blood flow while 1 Hz rTMS decreased it. A further controlled study in normal volunteers has confirmed that 1 Hz rTMS over frontal cortex induces relative decrements in bilateral frontal and striatal metabolism on PET. Two other studies in normal volunteers showed the different patterns of activation on PET of 1 Hz rTMS delivered over motor compared with prefrontal cortex. The most recent rTMS study used higher intensities of rTMS stimulation (110% MT) for a longer time (3 weeks)in an attempt to increase the response rate. This study randomized patients to 20 Hz vs. 1 Hz vs. sham stimulation, and results and regional brain activity correlates of response are currently being analyed. Thus, a number of promising and mechanistically novel treatment approaches have been prioneered in the Branch and the current effort is aimed at defining better optimal parameters for rTMS response and defining clinical and neurobiological markers of individual responsiveness.